The study of the human response to injury has been hampered by the inherent heterogeneity in the models and methods used. By studying a standard injury longitudinally, using individual patient‐level analysis, we endeavoured to better describe its dynamics. We analysed clinical variables, clinical laboratory and plasma cytokines from 20 patients at five time points. Clustering analysis showed two prototype patterns of cytokine behaviour: a concordant type, where cytokines behave the same way for all patients (notably IL‐0 and TNFα), and a variable type, where different patterns of expression are seen for different patients (notably IL‐8, IL‐6 and IL‐1RA). Analysis of the cytokines at the individual patient‐level showed a strong four‐way correlation between IL‐1RA, GCSF, MIP‐1β and MCP‐1. As it holds for most patients and not just on average, this suggests that they form a network which may play a central role in the response to gastro‐intestinal injuries in humans. In conclusion, the longitudinal analysis of cytokines in a standard model allowed the identification of their underlying patterns of expression. We propose that the two prototype patterns shown may reflect the mechanism that separates the common and individual aspects of the injury response.

Recent studies have pointed out that highly cationic histones released by PMNs netosis may be major agents in autoimmune lupus since they have high affinity to various kidney sites and can be expected to play a key role in autoimmune glomerular disease.

Similarly to antibodies, cationic peptides such a nuclear histone can also act as potent opsonic agents capable of binding by strong electrostatic forces to negatively charged domains in immune complexes and in complement components resulting in their endocytosis and deposition in various parts of the kidney. It is also proposed that to prevent such events, highly anionic heparin and heparinoids, may be effective drugs since these may effectively neutralize histones activities but provided that agents such as steroids, methotrexate and colchicine, all potent inhibitors of neutrophils functions, and antibodies to TH1 cytokines be essential to treat nephritis and to prevent kidney failure. However, the main cause of kidney damage is eventually caused by the plethora of toxic pro inflammatory agents delivered by activated neutrophils and macrophages.

The present study offers a novel approach that may explain the mechanisms of pathogenicity of the auto immune destructive disorder, Lupus Erythematosus. It is proposed that deposition of immune complexes and complement components in tissue is mediated by highly cationic histones released from neutrophils nets the phenomenon of netosis. Histones act a potent opsonic factor similar to antibodies which interact by strong electrostatic forces with negatively-charged domains in immune complexes and complements facilitating their deposition and also their internalization by hosts’ cells. However, the main cause of cell and tissue damage in Lupus is inflicted by the plethora of toxic pro inflammatory agonists released by neutrophils and by macrophages recruited to inflamed tissues by cytokines. The melioration of tissue damage may be initiated by highly anionic heparins, which neutralizes histones’ action if also combined with steroids, colchicin and methtorxate as well as by other agents which retard leukocytes migration and functions.

A novel hypothesis is presented to explain the pathogenesis of the multifactorial autoimmune disorder rheumatic fever (RF). It involves a synergistic interaction among streptococcal toxins, their cell wall components, M protein, immune complexes, complement components, cationic histones. These agents can act with cationic histones released by neutrophils during NETosis and bacteriolysis and can function as opsonic agents possessing properties similar to antibodies. Cationic histones can interact by strong electrostatic forces with negatively- charged domains on immune complexes and complement components. This allows their deposition and endocytosis in the myocardium, the heart valves, and in the joints. However, the main cause of cell and tissue damage observed in RF is due to a synergism among the plethora of pro-inflammatory substances released by activated neutrophils and macrophages. Cell damage may be mitigated to some extent by anionic heparins, heparinoids, and by anti-inflammatory drugs such as corticosteroids which counteract neutrophils and macrophage chemotaxis induced by cytokines.